Summary: Alcohol abuse is a major risk factor for diseases of the exocrine pancreas pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). One obstacle to understanding these diseases is the lack of clinically relevant mouse models. Feeding of an alcohol containing diet does not lead to spontaneous CP or PDAC in wild-type mice. However, we have observed that alcohol is sufficient to induce disease in mice with clinically relevant genetic alterations. Specifically, mice expressing in adult pancreatic acinar cells KrasG12D, which is the most prominent mutation observed in this disease, do not develop PDAC on a control diet but so when fed alcohol. Furthermore, mice expressing human PRSS1R122H, the most common genetic aberration associated with human hereditary pancreatitis, do not develop CP on a control diet but do after alcohol feeding. These new models are more clinically relevant that the currently available animal models. The goal of the proposed research is to improve our understanding of the mechanisms involved in the synergistic interaction of alcohol with clinically relevant genetic mutations. Although a large number of acute effects of alcohol have been suggested to be important for pancreatic disease development, in humans the diseases are only observed after prolonged abuse. Likewise, the effects of alcohol in these novel mouse models are chronic, not acute. We have formed a novel hypothesis that may explain our observations in these mouse models and the complexity of these diseases in humans. In preliminary studies, we observed increased accumulation of advanced glycation-end products in the pancreases of alcohol fed mice. AGES interact with the receptor for advanced glycation end-products (RAGE), which is expressed on pancreatic acinar and stellate cells. AGEs activation of RAGE has previously been found to be important in acute pancreatitis, in the development of PDAC in a model of developmentally expressed oncogenic Kras, and in multiple models of alcohol induced fibrosis developed in other organs such as the liver, heart, and blood vessels. Specific Aim #1 will test the hypothesis that RAGE is involved in the development of PDAC in the alcohol fed mice expressing oncogenic mutant KrasG12D. We hypothesize that in the case of PDAC, alcohol induce AGEs activate RAGE and elevate the levels of Ras activity thus initiating the Ras/inflammation feed-forward loop which drives transformation. We will evaluate the effects of inhibiting RAGE activation using both pharmacological and genetic approaches. Specific Aim #2 will test the hypothesis that advanced glycation end-products (AGEs) are involved in the development of CP in the alcohol fed mice expressing R122H. In the case of CP, we hypothesize that AGEs accumulation in the pancreatic tissue causes persistent inflammation and contributes to the observed damage. The results from this research will provide a foundation for further studies aimed at targeting RAGE for the prevention or treatment of these currently untreatable maladies.